Targeted Core Shell Nanogels for Triple Negative Breast Cancer The central goal of this project is to improve systemic therapies of cancer using soft nanomaterials that can deeply penetrate into tumors and deliver potent anticancer agents to targeted cancer cells. Many small-molecule therapeutics that were highly promising for cancer therapy, eventually failed clinical translation due to toxicity, poor solubility, stability and othr delivery related problems. Recent advances in nanoparticle drug carriers provide a unique opportunity to rescue these agents and enable their clinical application. This is the focal point of our research using nanocarriers that can incorporate such agents, and preferentially deliver them to tumors. Our group has successfully developed a novel platform for drug delivery that uses aqueous polymeric gel nanoparticles, core-shell nanogels (CSNGs). CSNGs are manufactured through a proprietary self-assembly process and can be readily filled with various drug payloads. They are water-swollen and are practically non- adhesive, which may diminish their off-target side effects. We hypothesize that (a) the systemic and tumor flow dynamics of CSNGs will be a function of their molecular architecture and mechanical properties (b) and that these properties can be rationally controlled to modify the PK, distribution and tumor penetration of the CSNGs and the drugs they deliver. We will focus our research efforts on using CSNGs in the triple negative breast cancer (TNBC), a disease that despite treatment advances, still has a very poor outcome. As targeting strategies we will use the novel single-domain polypeptide antagonists of the EGFR and HER3 that are frequently overexpressed in TNBC and are associated with higher risk of mortality in TNBC. We assembled a cross- disciplinary team of physician-scientists and experts in nanotechnology, pharmacology and chemoinformatics, and will focus our research efforts on using POx micelle therapeutics in TNBC, a disease that despite treatment advances has a very poor outcome. The specific aims are: 1. Determine how the molecular architecture and mechanical properties of polypeptide-based CSNGs affects their ability to load, deliver and release therapeutic cargos. 2. Determine how the structure and mechanical properties of the drug-loaded CSNGs affect the in vivo PK and tumor distribution of the drugs and nanogels in murine models of TNBC. 3. Develop EGFR and HER3 targeted drug-loaded CSNGs with maximal tumor penetration, maximal delivery of drug payload to tumors and potent anti-tumor activity in TNBC These integrative efforts allow to address major barriers in developing novel nanotechnology platforms for the treatment of TNBC, and facilitate our understanding of the cancer biology and the mechanisms of in vivo delivery. If successful, we will determine a new targeted formulation of chemotherapeutic drugs in CSNGs that may be highly effective in treatment of TNBC. The results will then be reviewed with our clinical advisors for further consideration of these formulations for translational and clinical development.